Innate immunity is the first line of defense designed to protect the host from invading pathogens, including HIV. We have previously demonstrated that suppression of natural killer (NK) cell function, which can be profound, is related to the stage of HIV infection as well as the level of HIV plasma viremia. Our studies reveal that HIV viremia impairs the cytolytic and non-cytolytic functions of NK cells and the cell surface expression of various receptors on NK cells. DNA microarray analyses of NK cells in the presence and absence of HIV envelopes demonstrate the up-regulation of several genes that are important in inducing apoptosis and suppression of cell proliferation. In vitro analysis of NK cell interactions with R5 and X4 HIV envelopes demonstrate profound suppression of NK cell cytolytic and secretory functions after exposure to HIV envelopes. Furthermore, exposure to HIV envelopes suppressed the expression of several genes critical for cell proliferation and generic NK cell function. Future studies will be focused on delineating the underlying mechanisms involved in the interaction between R5 and X4 HIV envelopes and NK cells. Signal transduction pathways that are abnormally regulated in the HIV viremic state have been identified by DNA microarray analyses of NK cells from HIV viremic patients. Further analysis also demonstrated an increased susceptibility to Fas-mediated apoptosis of NK cells from HIV viremic individuals. In vitro studies established increased expression of the CD95 (Fas) molecule on the surface of NK cells and elevated levels of sFASL (soluble Fas ligand) in serum as the major mechanisms that render NK cells from HIV viremic individuals susceptible to apoptosis. These NK cells express significantly higher levels of intracellular Ki67, indicating a higher level of cellular activation associated with the HIV viremic state. These observations suggest a profound effect of HIV viremia on NK cell proliferation, chemotaxis, and, ultimately, survival in vivo. Future experiments will focus on evaluating the turnover of NK cells in vivo and the relative susceptibilities of NK cell subsets to undergo apoptosis. Such experiments will help us to understand the nature of NK cell proliferation and turnover in the HIV viremic state